Ординатура / Офтальмология / Английские материалы / Eye Pathology An Atlas and Text_Eagle_2010

Chloroquine, hydroxychloroquine (plaquenil)- (bull's-eye maculopathy) Dose related, primary effect on RPE? - drug stored in melanin granules

Thioridazine (Mellaril) -high doses

Methoxyflurane (anesthetic)

Crystalline retinopathy, oxalate crystals Chloramphenicol (chronic use in cystic fibrosis)

Atrophy of maculopapillary bundle, cecocentral scotomas

Quinine

Tamoxifen: nonsteroidal antiestrogenbreast cancer therapy, flecklike retinopathy Nicotinic acid (Gass)- atypical nonleaking CME

Canthaxanthine (crystalline retinopathy)- tanning agent Others...

THE MACULA,

Definitions:

Macula: macula lutea-"yellow spot", nonspecific clinical term.

Darker on IVFA: xanthophyll, more lipofuscin and melanin in taller RPE cells

Fovea: "pit"- depression in retina, 1 DD in size

Foveola: Floor of pit, greatest retinal thinning, avascular; anatomy: only photoreceptors, outer nuclear layer, some Henle fibers,

Age Related Maculopathy (Age-related macular degeneration, senile macular degeneration, SMD, ARMD)

Major public health problem, leading cause of irreversible blindness in people over age 50 in developed world

More common in blue-eyed patients, rare in blacks: suggest pathogenic role of chronic light exposure

Chronic inflammation may play a role in pathogenesis. Inflammatory mediators and complement components found in drusen and damaged RPE cells. Strongly associated with a common variant of complement factor H (CFH) gene- Tyr402His polymorphism 5-7x increased risk of AMD in homozygotes

"DRY" ARMD

RPE degeneration, pigment clumping, areolar loss of RPE with concomitant degeneration of outer retina and involution of choriocapillaris; AREDS

"WET"ARMD:

Choroidal neovascular membranes (CNV), exudation, focal serous detachment of retina, hemorrhagic RPE detachment, organization of hemorrhage, subretinal scar formation (disciform degeneration) RPE cells contribute to collagen production in vascularized scar

A CLINICAL SPECTRUM: "wet" and "dry" variants can be found in same patient

Aging Changes in Bruch's Membrane:

Thickening, PAS positivity, focal calcification, drusen Drusen- a clinical marker for "sick" RPE

Focal deposits of extracellular debris located between the basal lamina of the retinal pigment epithelium and the inner collagenous layer of Bruch’s membrane. Complex composition, confusing classification schemes

Probably made by "sick" or stressed RPE cells Hard drusen (cuticular)

Globular excrescences of densely hyaline PAS (+) material Association with dry or atrophic ARMD has been questioned (Green)

Soft Drusenfound only in macula, amorphous membranous debris

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Diffuse drusen- very strong association with exudative ARMD (esp. basal laminar deposit)

Basal laminar deposit (very important variant of diffuse soft drusen)

May be quite extensive, but not evident clinically

Thick diffuse layer of abnormal 1000 Å banded basement membrane material ("curly collagen") located between plasma membrane and basement membrane of RPE.

Composition: laminin, type IV collagen, heparin sulfate proteoglycans

Appears as pink granular band between Bruch's membrane and RPE.

Very common pathologic finding in ARMD (84% "wet", 53% "dry", 19% control - Grossniklaus)

Predisposes to RPE detachment and tears, SRNVM, disciform degeneration May interfere with biochemical modulation of choriocapillaries by RPE, barrier to diffusion, bind or sequester angiogenesis factors, displaces RPE from blood supply

Basal Linear Deposit

Second type of diffuse soft drusen composed of a layer of multivesicular phospholipid material localized within Bruch's membrane external to RPE basement membrane. It is impossible to distinguish from basal laminar deposit without electron microscopy

Subretinal Neovascular Membrane (CNV, choroidal neovascular membrane) New vessels derived from choroid, extend through breaks in Bruch's membrane Vessels leak, bleed with resultant hemorrhagic RPE and/or retinal detachment Disciform scar caused by organization of hemorrhage by granulation tissue and collagenous connective tissue (disciform degeneration)

Propensity for foveal and parafoveal region

Excised membranes very difficult to orient histopathologically

Vascular Endothelial Growth Factor and VEGF inhibitors, OCT Hemorrhagic Detachment of the RPE-can mimic choroidal melanoma

Diseases with SRNVM, disciform scar formation

ARMD

Focal choroiditis ( e.g , presumed ocular histoplasmosis syndrome) Angioid streaks

Myopic degeneration Choroidal rupture Central serous (rare) Dominant drusen Choroidal tumors

Juvenile disciform degeneration

Ocular Histoplasmosis Syndrome (POHS)

Triad:

Disciform degeneration of macula, peripapillary atrophy, peripheral punched-out spots

Focal chronic choroiditis, organisms rarely found

Macular Holes (Idiopathic)

Shrinkage of prefoveal cortical vitreous exerts lateral traction on retina causing localized foveal detachment, then hole (fibrocellular membranes rarely found) Better VA after surgery reflects smaller size of sealed hole and resorption of SRF

Classification of macular holes (Gass)

Stage I- foveal detachment (impending hole or macular cyst) – about 50% progress

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Stage IIearly hole formation

Stage IIIfull thickness hole with vitreofoveal detachment Stage IV- full-thickness hole with posterior vitreous detachment

Cystoid Macular Edema (CME)

Multiple cystoid spaces in macula with petalloid appearance on IVFA Irvine-Gass Syndrome – post cataract surgery

Very high incidence with iris supported IOL's

Secondary finding over choroidal tumors, especially hemangioma Occurs with peripheral uveitis, peripheral tumors

OCT and anti-VEGF therapy (Lucentis, Avastin), intravitreal Kenalog® Initial intracellular edema within Mueller cells (Fine, Brucker)

Ophthalmic lasers

Argon, krypton, diode: thermal coagulation.(Light absorbed by pigment, converted to heat)

Blue argon wavelengths absorbed by yellow macular pigment, damage retina Green argon wavelengths absorbed by blood, melanin

Red krypton wavelengths absorbed by melanin, not by blood or luteal pigment YAG: short pulse mode does not rely on thermal coagulation; optical breakdown "explosion" physically disrupts tissues

TTT (transpupillary thermotherapy), diode laser, large spot size, slow delivery, thermal effect

Excimer- molecular disruption

Retinitis pigmentosa (primary pigmentary retinopathy)

An extremely large heterogeneous group of diseases sharing:

Progressive photoreceptor degeneration typically leading to blindness by middle age

Rods affected more severely than cones in early disease

Night blindness and peripheral field loss, tunnel vision, blindness Attenuation of retinal vessels, waxy pallor of optic disc, bone spicule pigmentation in peripheral fundus

Posterior subcapsular cataract, macular edema, optic disk drusen

Genetics

Sporadic 39%, dominant 20%, recessive 37%, sex-linked 4%, Consanguinity 30-40%

Severity: Autosomal dominant< autosomal recessive < X-linked

More than 150 genes cause RP and related disorders (genes located on chromosomes 1, 3, 4, 5, 6, 7, 8, 11, 14, 15, 16, 17, 19, and X (most identified by linkage studies)

45 genes cause nonsyndromic RP genes. Examples: RHO, PDE6A, PDE6B, CNGA1, SAG, RPE65, RLBP1, ABCA4, RGR, RDS, ROM1, PROML1, NRL, CRX, RP1, RP2, RPGR, CRB1, and TULP1.4

Some encode proteins involved in rod phototransduction cascade: Rhodopsin (RHO)

15-20%% of patients with dominant RPmost single AA substitutions (missence mutations), most common His-23-Pro

subunits of rod c-GMP-phosphodiesterase subunit of c-GMP-gated cation channel arrestin guanylate cyclase activating protein

Others encode for proteins of unknown function Peripherin/RDS

(Mutations also found in occasional patients with macular dystrophies such as Best's Vitelliform or Butterfly dystrophy)

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(Null mutation cause photoreceptor degeneration in RDS mice) ROM 1, Myosin 7A, RPGR13% of cases, NRL

Histopathology

Primary photoreceptor degenerationatrophy involves outer retina Loss of photoreceptors, ONL

Bone spicule pigmentation caused by intraretinal RPE migration

TEM: intraretinal formation of new perivascular "Bruch's membrane" Macromelanosomes (PR atrophy may allows RPE to invade retina)

RPE usually fairly well preserved

Variants of Retinitis Pigmentosa

Leber Congenital Amaurosis (congenital blindness of early onset RP)- 8 genes identified – Briard dogs with RPE65 gene canine model cured by gene therapy

CEP290most common gene – 20% of cases Sector retinitis pigmentosa

Usher's Syndrome (association of RP and hearing loss- 3 types) Retinitis pigmentosa with Coats'-like response

Retinitis punctata albescens

X-linked Juvenile Retinoschisis (Xp22.2) retinoschisin Split in nerve fiber layer (in periphery)

Stellate maculopathy does not stain with fluorescein: OCT all layers ? abnormal vitreous-like material in retina (Brownstein)

Macular dystrophies (hereditary, bilateral)

Fundus flavimaculatus (Stargardt's disease) 1p21-p13

Once thought to be primary RPE disease, but causative ABCA4 gene is expressed only in photoreceptor outer segments. Defect in abcr transport protein leads to accumulation of toxic vitamin A derivative A2-E in outer segments that poison RPE's phagolysosomal system, leading to accumulation of lipofuscin in RPE.

Autosomal recessive, onset in teens

Yellow pisciform flecks in RPE, atrophic macular degeneration RPE PAS+, cells contain massive amounts of abnormal lipofuscin Posterior RPE cells massively enlarged

"Dark" choroid on IVFA, vermilion fundus due to RPE lipofuscin Fundus flavimaculatus without macular lesion lacks abnormal pigment

Best's disease (Vitelliform macular dystrophy)

Dominant, bestrophin gene (BEST1) on chromosome 11q (11q13)

Some cases of Adult vitelliform caused by defects in peripherin/RDS gene Egg yolk lesion "scrambles" with age, Abnormal EOG

RPE disease with increased amounts of abnormal lipofuscin

Sorsby Macular Degeneration

Dominant presenile macular degeneration; similar to ARMD clinically Massive deposit of BLD-like material beneath RPE

Defect in gene (chromosome 22) encoding TIMP 3 (Tissue inhibitor of metalloproteinase 3)

Theorymutant TIMP3 could inhibit MP that normally catabolize Bruch's membrane too well.

Kearns-Sayre Syndrome

Progressive external ophthalmoplegia, heart block, atypical pigmentary retinopathy; large deletion in mitochondrial DNA

"Salt and pepper" retinopathy, no bone spicules, involves posterior fundus,

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Other mitochondrial cytopathies (MERRF, MELAS) occasionally affect retina

Oguchi Disease

Form of stationary night blindnessgolden fundus reflex - Mizuo-Nakamura phenomenonmutations in arrestin or rhodopsin kinase; some patients may develop late retinal degeneration

Gyrate atrophy (autosomal recessive ornithine-delta-aminotransferase deficiency) Hyperornithinemia, ornithine aminotransferase deficiency

Ornithine may act as an RPE toxin

Choroideremia

X-linked degeneration of RPE, choroid and photoreceptors (primary site unknown) Asymptomatic female carriers have patchy pigmentation and RPE and choroidal degeneration.

CHM gene which encodes for Rab escort protein-1 (REP1),

Mucopolysaccharidoses

Inherited deficiencies of catabolic lysosomal exoenzymes. Fibrillogranular and multimembranous inclusions.

Outer retinal atrophy due to RPE degeneration; marked in Sanfilippo (MPS III); mimics primary retinitis pigmentosa

Sphingolipidoses

Syndromic RP: Bardet-Biedl, Senior Loken, Bassen-Kornzweig, Bietti corneoretinal crystalline dystrophy, cystinosis, neuronal ceroid lipofuscinosis, Refsum disease, autosomal dominant cerebellar ataxia type II, Joubert syndrome, Hallervorden Spatz, etc.

Diabetes mellitus

Diabetic retinopathy Microangiopathy

Loss of capillary pericytes (Normal endo/pericyte = 1/1) Role of sorbitol in pericyte loss

Thickening of capillary basement membranes Capillary nonperfusion (capillaries are totally avascular)

Angiogenic factor (VEGF- vascular endothelial growth factor) produced by ischemic retina

Neovascularization of disk and retina

Microaneurysms

Seen in diabetes and other retinal diseases with ischemia

DM: mainly posterior pole, CRVO: throughout retina, others: periphery 50-100µ, most not ophthalmoscopically visible (One sees associated hemorrhage)

Increased number of endothelial cells (proliferation versus migration) Wall initially thin and leaky, thickens, PAS (+), eventual occlusion

Background retinopathy

Hemorrhages, hard exudates, retinal edema

Preproliferative retinopathy

Many cotton wool spots are a marker for retinal ischemia Intraretinal Microvascular Abnormalities (IRMA)

Proliferative retinopathy

Neovascularization of disk, retina, iris; angiogenic factor (VEGF) New vessels proliferate on scaffold of partially detached vitreous Progressive vitreous detachment rips vessels causing subhyaloid and vitreous hemorrhage

Scarring and organization of hemorrhage produces vitreoretinal

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Traction, tractional retinal detachment

Diabetic iridopathy

Iris neovascularization (Rubeosis iridis): Higher incidence post-lensectomy

Lens acts as barrier to anterior diffusion of angiogenic factor

Diabetic lacy vacuolization of iris pigment epithelium

Glycogen-filled cysts in IPE, contents PAS (+) , diastase-sensitive

Basement membrane thickening

Retinal capillaries

Nonpigmented ciliary epithelium (can be diagnostic)

Corneal epithelial basement membrane (epithelium can desquamate as sheet)

Diabetic cataract

Role of aldose reductase, sorbitol

Albinism (oculocutaneous and ocular albinism)

Foveal hypoplasiaoccurs in varieties caused by different genes), iris transillumination

X-linked ocular albinism: macromelanosomes in RPE, skin

Sickle Cell Retinopathy

Proliferative retinopathy most severe in Hb SC disease

Blockage of retinal vessels by sickled cells leads to nonperfusion of temporal peripheral retina, peripheral shunts

Neovascular fronds (sea fans) develop at junction between perfused posterior and nonperfused peripheral retina

Late stages: hemorrhage, secondary retinal detachment

Black sunburst sign: chorioretinal scar with RPE proliferation secondary to old hemorrhage

Peripheral Retinal Degenerations

Peripheral microcystoid degeneration (typical) Very common, found in all adults > 20 years Blessig-Iwanoff cysts in outer plexiform layer

Filled with hyaluronidase-sensitive acid mucopolysaccharide Coalescence of cysts leads to typical degenerative retinoschisis

Reticular cystoid degeneration

18% of adults, bilateral in 41%

Posterior to, and contiguous with typical microcystoid Finely stippled, inferior temporal quadrant

Cysts in nerve fiber layer

Can lead to reticular degenerative retinoschisis

Typical degenerative retinoschisis

1% of adults, inferotemporal retina

Split in outer plexiform layer, large holes in outer layer Vessels in inner layer; irregular outer layer has beaten-metal appearance, turns white on scleral depression

Peripheral Chorioretinal Degeneration

(Paving stone or Cobblestone degeneration, CRA) Incidence 27% over age 20

Probably caused by choroidal vascular insufficiency

Pattern of outer ischemic atrophy: loss of choriocapillaris, RPE, outer retina

Chorioretinal scar: outer retina fused to bare Bruch's membrane Lattice Degeneration (vitreoretinal degenerative process)

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6-11% of population

Sharply demarcated, circumferentially-oriented areas of retinal thinning, anterior to equator, vertical meridians

Secondary RPE proliferation, Only 12% of lesions have white lines

Histology:

Discontinuity in ILM

Retinal thinning with loss of inner layers Overlying pocket of liquefied vitreous

Vitreous condensation and gliosis at margins of pocket Sclerosis of major vessels in lesion, capillary occlusion RPE hypertrophy, hyperplasia and migration

Lattice predisposes to retinal breaks (firm adherence of vitreous to margin of lesions)

Posterior margin breaks, lattice in operculum (30%)

Pars Plana Cysts

Split between pigmented and nonpigmented layers of ciliary epithelium Aging – cysts contain hyaluronic acid

Multiple myelomacysts filled with myeloma proteins are white after fixation

Retinal detachment

Fluid collects in potential space between inner and outer layer of optic cup; retinal separation a better term.

Artifactitious versus real RD in tissue sections (Almost all unopened eyes fixed by immersion in formaldehyde have an artifactitious retinal detachment.)

True retinal detachment

Photoreceptor degeneration, eosinophilic proteinaceous fluid in subretinal space, RPE budding or papillary proliferation with chronicity

Artifactitious retinal detachment:

No fluid in subretinal space, photoreceptors healthy, RPE granules adhere to outer segments

Rhegmatogenous retinal detachment Secondary to retinal holes and breaks

Most holes due to vitreous traction in eyes with posterior vitreous detachment, vitreous degeneration, lattice degeneration

Horseshoe tears- “the horse always walks toward the optic disk” Incidence of retinal holes: 4.8-10% (path), 5.8-13.7% (clinical) Important prognostic criteria: Symptoms, subclinical detach, aphakia

Exudative retinal detachment (serous)

Tumors (most melanomas, hemangiomas, metastases)

Uveal effusion, Harada's, toxemia of pregnancy, oxygen toxicity

Tractional retinal detachment

Proliferative diabetic retinopathy

Chronic retinal detachment

Funnel or morning glory configuration, photoreceptor degeneration, gliosis, macrocystic degeneration; may have secondary pigmentary retinopathy Proliferative vitreoretinopathy,

Vitreous

Posterior vitreous detachment

63% incidence in 8th decade, rare before age 55

7.5% have associated vitreous hemorrhage, 15% have retinal breaks

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Flashes, floaters, Weiss ring (peripapillary condensation) Important role in retinal detachment

Vitreous opacities

Hyaloid remnants (muscae volitantes, or mouches volantes-"flying flies")

Vitreous hemorrhage

Blood breakdown products in chronic hemorrhages ("ochre membrane") erythrocyte ghost cells, hemoglobin spherules, hemosiderin-laden macrophages: Hemolytic, ghost cell glaucoma,

Complications: organization leading to tractional RD, hemosiderosis (repeated hemorrhage)

Causes: trauma, retinal tears, PVD, diabetic retinopathy, sickle cell, Eales', disciform degeneration of the macula, tumors, Terson's syndrome (subarachnoid hemorrhage)

Asteroid hyalosis (Benson disease, Scintillatio nivea) 2% incidence, unilateral (80%), increases with age Generally does not interfere with vision

Spherules of calcium hydroxyapatite attached to vitreous framework (Not calcium soap )

Gray spheres with Maltese cross birefringence on polarization Synchisis Scintillans (Cholesterolosis bulbi)

Rare, bilateral, blind eyes, young patients Cholesterol crystals derived from old hemorrhage

Not fixed to vitreous framework, sinks to bottom of globe

Primary Amyloidosis Of The Vitreous

Vitreous involvement in Familial Amyloidotic Polyneuropathies (FAP's) Amyloid comprised of mutant transport protein transthyretin (prealbumin) Several missence (AA substitutions) mutations (e.g. common Met 30 variant Often presents in elderly patients with no family history

Associations include cardiac disease, amyloid neuropathy, carpal tunnel syndrome Amyloid probably enters via retinal vessels

Intravitreal Tumor Cells

Retinoblastoma

Vitreous seeding common in advanced cases, poor prognostic sign

Primary Lymphoma of CNS and Retina (NHL-CNS)

("ocular reticulum cell sarcoma"- old, incorrect, outdated term) Bilateral vitritis, CNS lymphoma, dementia

Poor prognosis (mean survival 22 months) Most are large B cell lymphocytic lymphomas

Primary CNS lymphoma spares uvea, but sub-RPE deposits are common No systemic involvement outside CNS

Diagnostic vitrectomy reveals:

Atypical lymphocytes with prominent nucleoli, mitoses, abundant cellular necrosis

NOTE: Systemic lymphomas can involve vitreous secondarily in rare cases, but; uveal infiltration is more typical in such cases

Whipple Disease- rarely mimics primary CNS lymphoma with bilateral vitritis, dementia, Cells PAS (+), contain bacteria Tropheryma whippelii

Metastatic Skin melanoma- predilection for retinal and vitreous metastasis

Vitreous Membranes (proliferative vitreoretinopathy, PVR)

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RPE, glial cells, myofibroblasts

Vitreous detachment allows cells to proliferate on inner and outer surface of retina, along scaffold of detached vitreous

Membranes cause fixed folds, inoperable RD

Proliferation on posterior face of detached vitreous responsible for funnel shape of chronic RD

Anterior variant of PVRorganization of vitreous on pars plana inaccessible to vitrectomy; anterior loop retinal detachment, posterior traction on iris

Surface Wrinkling Retinopathy (Cellophane retinopathy) Epiretinal glial proliferation; contraction of membrane folds ILM

Intraocular Tumors

Uveal Malignant Melanoma

Most common primary intraocular tumor in white adults

Risk Factors

Race

Uveal malignant melanoma is predominantly a tumor of blue-eyed Europeans Incidence in U.S. whites is 8.5 times greater that blacks

Incidence in USA is 21 times greater than in Taiwan (6 vs. 0.28/million) Tumors in blacks are larger, more pigmented, more necrotic and have same survival as tumors in whites.

Age

Incidence increases with age, median age at diagnosis53 (AFIP), 59 (COMS) Larger tumors, poorer survival with increasing age:

* Survival after enucleation [ Non tumor deaths excluded]

Male = female in COMS study

Predisposing Lesions

Congenital ocular or oculodermal melanocytosis [Nevus of Ota] 1/400 lifetime risk of MM in Caucasians

Uveal neviestimated rate of malignant transformation- 1/10,00015,000/ year Neurofibromatosis

Dysplastic nevus syndrome (familial atypical mole melanoma syndrome) Ultraviolet lightmore common in blue eyes, inferior iris

Chemical carcinogens?? Pregnancy

BDUMP Syndrome- (Bilateral diffuse uveal melanocytic proliferation associated with systemic malignancy).

Remote effect of disseminated malignancy

Bilateral diffuse thickening of uvea with pigmented nodules. "giraffe skin" fundus Melanomas may arise from generalized low-grade spindle cell proliferation

Clinical Presentation of Uveal Melanoma

Incidental Finding on routine examination Visual Loss

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